As everyone knows, angiogenesis is of vital importance to the growth and transfer of tumors; hence, the tumor vessel system has become a valuable tumor therapy target. Generally speaking, the anti-tumor drugs that target tumor vascular system mainly comprises an anti-angiogenic agent and a vascular disrupting agent (VDAs), in which the former can inhibit the growth of new tumor vessels, and the latter is used for targeting and destroying the existing vascular net that supplies oxygen and nutrients to tumor cells. The tumor vessel has an abnormal structure different from the normal vessel, its endothelial cells are fast proliferating, and the vascular wall gets thin and has high permeability, resulting in high blood stream resistance. VDAs can be selectively acted on the vascular endothelial cells of the tumors, interfering with its the binding site of adhesion and microtubule cytoskeleton, thereby affecting the migration, adhesion and proliferation of endothelial cells, resulting in increase in the protein permeability and gap pressure of blood vessels, causing blood plasma leakage, reduction of blood vessel diameter and improvement in blood viscosity, and finally leading to tumor necrosis through further slowing down in blood stream and blocking in supply of oxygen and nutrients.
VDAs can be divided into ligand targeted VDAs and small molecular VDAs, in which the former consists of a targeting part (e.g., antibodies, peptide or growth factors) and an effector part (which can kill tumors via different mechanisms), and the latter can be further divided into flavones and microtubulin binding agent. Plinabulin (KPU-2, NPI-2358, Chinese name Plinabulin) developed by Nereus Pharmaceuticals Co., Ltd. is a microtubulin binding agent, which is a synthetic derivative of low molecular cyclo-dipeptide Phenylahistin or halimide derived from marine Aspergillus sp, and can selectively act. on the neighborhood of colchicine binding site in endothelial microtubulin to inhibit the polymerization of microtubulin, block off microtubule assembly, thereby destroying the cytoskeleton of endothelial cells, inhibiting the blood stream of tumors without damaging the normal blood vessel system.
Plinabulin binds to the neighborhood of colchicine binding site of microtubulin, acting on MM cells, making MM cells stop growing at the early stage of caryomitosis, thereby inducing cell death. Plinabulin also inhibits the formation of microtubule and the migration of endothelial cells and MM cells, resulting in disfunction of the tumor vascular system. Plinabulin can induce the death of cancer cells without affecting the vigor of other normal monouclear cells.
The chemical structural formula of Plinabulin is as below:

The molecular formula of Plinabulin is C19H20N4O2, the molecular weight is 336.39, the CAS No. is 714272-27-2. It has good stability.
Deuterium is a stable and non-radioactive isotope of hydrogen, with molecular weight of 2.0144. As the content of deuterium in the generated deuterated compound is far higher than the content of 0.015% as in natural world, hence, it can be deemed as a novel compound. Deuteration in drugs improvement is also accepted by United States Patent and Trademark Office, such as deuterated Rimonabant, Mosapride, Oxybutynin and so on have been approved.
Studies indicate that deuterium is the best bioisostere at present in the design of drugs. Under the action of deuterating, the drug efficacy and toxicity difference caused by different populations and genders can be reduced, the individual difference between patients can be reduced, the adverse reaction events can be reduced through reducing harmful metabolites, and genotoxicity can also be reduced, hence, the action of deuterating has been widely applied to human clinical study and pharmacokinetic study in the drug research and development process. At present, there are many international pharmaceutical enterprises engaging in the research and development of new deuterated drugs, and many deuterated drugs have entered into the clinical experiment, such as CTP-347 and CTP-499.
The important characteristic of deuterium is that its shape and volume in drug molecules are basically the same as those in hydrogen. If the hydrogen in the drug molecules is selectively replaced with deuterium, generally, the deuterated drugs will retain the original biological activity and selectivity. It has been proven by experiments that the binding of the carbon-deuterium bond is more stable than that of the carbon-hydrogen bond. The carbon-deuterium bond formed by deuterium carrying neutrons and carbon vibrates at lower frequency, as a result, it is stronger than the carbon-hydrogen bond. Such increase in strength can directly affect the absorption, distribution, metabolism, discharge and other attributes of some drugs, thereby improving the effectiveness, safety and tolerance of drugs. Hence, theoretically, it is considered that if a certain carbon-hydrogen bond to be decomposed in the drug molecules is deuterated to be the corresponding carbon-deuterium bond, the decomposition process will be delayed, making the action time of the deuterated drugs in bodies longer, which leading to a drug with superior effect to the original one.